Version August 2024
INTRODUCTION — Bacterial meningitis is more common in the first month than at any other time of life [1]. Despite advances in infant intensive care, neonatal meningitis remains a devastating disease.
The epidemiology, etiology, clinical features, and diagnosis of bacterial meningitis in the neonate will be discussed here. The treatment, prognosis, and complications of neonatal bacterial meningitis are discussed separately, as is bacterial meningitis in older children:
●(See "Bacterial meningitis in the neonate: Treatment and outcome".)
●(See "Bacterial meningitis in the neonate: Neurologic complications".)
●(See "Bacterial meningitis in children older than one month: Clinical features and diagnosis".)
●(See "Bacterial meningitis in children older than one month: Treatment and prognosis".)
EPIDEMIOLOGY
●Incidence – The incidence of bacterial meningitis in neonates (infants <1 month) ranges from 0.25 and 0.32 per 1000 live births, depending upon the definition used [2-6]. The incidence has declined substantially since the 1970s, largely due to prevention of early-onset group B streptococcal (GBS) disease through screening efforts, intrapartum antibiotic prophylaxis, and prompt evaluation of neonates with well-defined maternal risk factors. In the same time period, preterm neonates have accounted for a growing number of cases: as many as 30 percent of all cases of neonatal meningitis in contemporary reports [5,7]. (See "Prevention of early-onset group B streptococcal disease in neonates".)
Bacterial meningitis occurs in as many as 15 percent of neonates with bacteremia. Among infants with invasive GBS disease, 5 to 10 percent with early-onset and approximately 25 to 30 percent of those with late-onset infections have meningitis [8-11]. (See "Group B streptococcal infection in neonates and young infants".)
During the second month after birth, the incidence of meningitis declines by approximately 50 percent; however, these young infants continue to have increased risk relative to older infants and children [12]. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis".)
●Risk factors – Risk factors for neonatal meningitis are largely the same as for neonatal sepsis occurring at sites outside the central nervous system. They include low birth weight, preterm birth, premature and/or prolonged rupture of membranes, maternal intra-amniotic infection, and others, as discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors' and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Risk factors'.)
Risk factors for late-onset infections are not as well established. Meningitis can occur from spread of a gram-negative infection (eg, urinary tract infection progressing to bacteremia and meningitis). (See "Urinary tract infections in neonates".)
In addition, preterm neonates with intraventricular hemorrhage and/or intraventricular hardware are at increased risk of late-onset meningitis [13]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)
In preterm neonates without these risk factors, late-onset meningitis is an uncommon manifestation of nosocomial infection. In one study of 4731 episodes of late-onset nosocomial infection in preterm neonates (22 to 26 weeks gestation), meningitis accounted for only 3.5 percent of the episodes [14].
MICROBIOLOGY — In high-income countries, group B Streptococcus (GBS), Escherichia coli, and other gram-negative bacilli are the most common causes of neonatal meningitis (table 1) [6,7,10,15-20].
In prospective surveillance studies, GBS and E. coli accounted for approximately 65 to 75 percent of all cases of early-onset meningitis (ie, onset within 72 hours of birth) [17,21]. When E. coli meningitis occurs after six days of age, galactosemia should be excluded. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Epidemiology' and "Galactosemia: Clinical features and diagnosis".)
Gram-positive organisms other than GBS (eg, Enterococcus, coagulase-negative staphylococci, Staphylococcus aureus, Listeria monocytogenes, group A Streptococcus, and alpha-hemolytic streptococci) contribute to the total disease burden, particularly among preterm infants [22]. However, none of these organisms accounts for more than 1 to 4 percent of cases overall [21,23]. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Microbiology'.)
Gram-negative organisms other than E. coli (eg, Klebsiella, Enterobacter, Citrobacter, Serratia marcescens, and Salmonella) contribute to the total disease burden, either as colonizers of the gastrointestinal tract or from exogenous sources [24]. Cronobacter sakazakii meningitis has been linked to the consumption of powdered infant formula [25].
Neisseria meningitidis, Streptococcus pneumoniae, and nontypeable Haemophilus influenzae also rarely cause meningitis in newborn infants. These pathogens are the most common causes of bacterial meningitis in older children. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Microbiology'.)
Anaerobic pathogens, especially Bacteroides fragilis, are a consideration in neonates with clinical and laboratory findings suggestive of meningitis with negative routine culture results [26].
Pasteurella multocida should be considered in the differential diagnosis, especially if there was preceding contact with companion animals such as dogs and cats (typically by licking rather than a bite) [27]. (See "Pasteurella infections", section on 'Epidemiology'.)
In low- and middle-income countries, the microbiology of bacterial meningitis in neonates varies geographically, but GBS remains a prominent cause [28].
CLINICAL FEATURES — The clinical presentation of neonatal meningitis is indistinguishable from that of neonatal sepsis without meningitis. The most commonly reported clinical signs are temperature instability, irritability or lethargy, and poor feeding or vomiting [29].
Temperature instability — Temperature instability is the most common finding. Temperature instability encompasses fever (rectal temperature >38°C) or hypothermia (rectal temperature <36°C). Term infants are more likely to have fever, whereas preterm infants are more likely to have hypothermia [30]. Temperature instability is present in approximately 60 percent of neonates with bacterial meningitis [24,29].
Neurologic findings — Neurologic signs of neonatal meningitis may include irritability, lethargy, poor tone, tremors or twitching, and seizures. Irritability is common and present in up to 60 percent of patients [29]. Seizures have been reported as a presenting feature in 20 to 50 percent of infants with neonatal meningitis, more commonly with gram-negative compared with gram-positive pathogens [31]. Seizures usually are focal and may be subtle (eg, lip smacking or eye deviation) [29].
Bulging fontanelle and nuchal rigidity are not common findings at the time of initial presentation but are found in approximately 25 and 15 percent of affected neonates, respectively [24,29]. However, when these findings are present, they should raise concern for meningitis.
Other findings — Other findings of neonatal bacterial meningitis and their approximate frequencies are listed below [24,29]:
●Poor feeding or vomiting – 50 percent
●Decreased activity – 50 percent
●Respiratory distress (tachypnea, grunting, flaring of the nasal alae, retractions, decreased breath sounds) – 33 to 50 percent
●Apnea – 10 to 30 percent
●Change in stool frequency or consistency – 20 percent
EVALUATION
Sepsis evaluation — Because the clinical presentation of bacterial meningitis in the neonate is nonspecific, neonates with suspected bacterial meningitis should undergo a full laboratory evaluation for sepsis. This includes:
●Complete blood count with differential (optional)
●Blood culture
●Urine culture (if ≥72 hours old) [24]
●Lumbar puncture (LP) (see 'Lumbar puncture' below)
Examination of the cerebrospinal fluid (CSF) is necessary to establish the diagnosis of bacterial meningitis. (See 'Diagnosis' below.)
The following sections provide a detailed discussion of the CSF examination. Other components of the laboratory evaluation for neonates with suspected sepsis are discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests' and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Evaluation'.)
Lumbar puncture
Timing of lumbar puncture — All neonates with clinical signs concerning for sepsis should undergo LP to evaluate for meningitis. Ideally, the LP should be performed before or soon after starting antibiotic therapy. However, in some cases, the neonate may be too unstable to safely undergo LP at the time of the initial diagnostic evaluation. In these instances, antimicrobials should be provided in doses sufficient for the treatment of meningitis, until the neonate is stable enough to tolerate the procedure. Empiric treatment is discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)
Procedure — Details of the LP procedure are provided separately. (See "Lumbar puncture in children".)
Tests to perform — The following tests should be performed on the CSF:
●Cell count and differential (see 'Interpretation of CSF parameters' below)
●Protein and glucose (see 'Interpretation of CSF parameters' below)
●Gram stain and culture (see 'Gram stain and culture' below)
●Multiplex PCR testing (if available) (see 'Molecular methods' below)
●Herpes simplex virus (HSV) PCR if there are clinical concerns for HSV infection and/or CSF pleocytosis (see 'Testing for herpes simplex virus' below and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV')
While preliminary data suggest measuring other inflammatory markers (eg, procalcitonin) in the CSF might aid in the diagnosis of neonatal meningitis, additional data are needed before adopting this into routine practice [32].
Interpretation of CSF parameters — Interpretation of CSF studies in newborns can be challenging. The range of normal values for CSF parameters is different for neonates than for older infants and children and also varies slightly by gestational and chronologic age [33-39].
●CSF cell count – In the neonate, a CSF white blood cell (WBC) count >15 cells/microL is consistent with meningeal inflammation, and bacterial meningitis should be a consideration (ie, this finding warrants empiric antibiotic therapy pending culture results) [33,36,37,40,41]. However, it is important to recognize that neonatal meningitis occasionally can occur with normal CSF WBC count, and some neonates with CSF WBC >15 cells/microL do not have meningitis. In one study, CSF WBC >20 cells/microL had a sensitivity of 66 percent and a specificity of 78 percent for identifying neonates with culture-proven meningitis [41]. In this study, the median CSF WBC among neonates with culture-proven meningitis was 180 cells/microL (range 2 to 1523).
The CSF WBC count is typically greater in gram-negative meningitis compared with gram-positive meningitis, though there is considerable overlap [42].
If the is an unequivocal CSF pleocytosis (eg, CSF WBC >100/microL with a neutrophil predominance), a provisional diagnosis of meningitis can be made. However, if the CSF cell count is equivocal (eg, CSF WBC 12 to 25/microL), the interpretation should be made in the context of the neonate's overall clinical status and clinical course. If the initial CSF is obtained so early in the course that CSF findings of bacterial meningitis are not definitive, repeating the LP 24 to 48 hours later may provide clarity because signs of inflammation in the CSF increase. When the meninges are inflamed, the second LP always shows a pleocytosis and other parameters are consistent with the diagnosis of meningitis. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Repeat lumbar puncture'.)
●Traumatic lumbar puncture – If the LP is traumatic, the neonate should be treated presumptively for meningitis, pending results of CSF culture. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Antimicrobial therapy'.)
Adjusting the CSF WBC count to account for high numbers of red blood cells in a traumatic LP does not aid in the diagnosis or exclusion of meningitis [43].
●CSF protein – CSF protein levels >100 mg/dL in term neonates and >125 to 150 mg/dL in preterm neonates are consistent with bacterial meningitis [44,45]. However, CSF protein levels are highly variable in neonates both with and without meningitis [33,34,40]. In a study that analyzed data on nearly 3500 uninfected term neonates, the median CSF protein concentration was 66 mg/dL and the upper limit of normal (ie, 95th percentile) was 118 mg/dL [36].
Other conditions that can cause elevated CSF protein include intracranial hemorrhage, parameningeal infections (eg, brain abscess), and congenital infections (eg, congenital cytomegalovirus [CMV] infection) [46]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Laboratory findings'.)
●CSF glucose – CSF glucose values are highly variable in neonates [33,34,36]. A low CSF glucose level concentration (ie, <60 percent of the blood glucose level or <30 mg/dL [1.7 mmol/L] in a term infant or <20 mg/dL [1.1 mmol/L] in a preterm infant) is consistent with bacterial meningitis. However, this is neither a sensitive nor specific finding. In addition, the ratio of CSF to serum glucose is not useful in acutely ill neonates since their serum glucose may be increased secondary to stress or administration of intravenous glucose before the time of evaluation.
Microbiologic tests
Gram stain and culture — The presence of an organism on CSF Gram stain strongly suggests the diagnosis of bacterial meningitis and has the advantage of providing a presumptive etiologic diagnosis before culture results are available. However, the absence of organisms on Gram stain does not exclude the diagnosis. Neonates with culture-proven meningitis can have negative Gram-stained smears, especially if the concentration of organisms in the CSF is low [47].
The CSF culture is the definitive method for confirming the diagnosis of meningitis, as discussed below. (See 'Diagnosis' below.)
Molecular methods — Molecular methods are increasingly used to assist in the diagnosis of central nervous system infections in infants and children. Multiplex or panel-based nucleic acid amplification tests are now available that test for multiple bacterial and viral pathogens simultaneously in a single CSF sample (eg, FilmArray meningitis/encephalitis [ME] panel [BioFire]) [48,49]. The FilmArray ME panel tests for 14 different pathogens, including group B Streptococcus, E. coli (K1 serotype only), Listeria monocytogenes, Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, HSV-1, HSV-2, CMV, enterovirus, human parechovirus, human herpesvirus 6, varicella zoster virus, and Cryptococcus.
Molecular tests are highly sensitive and specific, though false-positive and false-negative results can occur. In a study that analyzed 62 CSF samples from infants <3 months old, the multiplex ME panel was more sensitive than bacterial culture, which was attributed to several infants having received prior antimicrobial therapy before CSF was obtained [49].
If a multiplex panel is performed, it should be used in conjunction with standard microbiologic tests (eg, cultures of CSF and blood). Multiplex panels do not detect all causes of central nervous system (CNS) infection, nor do they provide any information on antimicrobial susceptibility of the pathogen.
In addition, multiplex PCR testing for HSV-1 and HSV-2 is less sensitive than most standard HSV PCR assays. Thus, we suggest testing specifically for HSV if there is clinical suspicion for HSV infection. (See 'Testing for herpes simplex virus' below.)
Testing for herpes simplex virus — Testing for HSV infection is often warranted in neonates undergoing evaluation for bacterial meningitis, particularly those with CSF pleocytosis and/or signs concerning for meningitis. If there is clinical suspicion for HSV infection, testing includes CSF HSV PCR plus additional blood tests and surface viral cultures. The evaluation for neonatal HSV infection is discussed in detail separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)
DIAGNOSIS — Neonatal meningitis should be suspected in any infant younger than one month of age who presents with clinical findings of sepsis or meningitis and in neonates who have positive blood cultures. The clinical findings can be subtle and/or limited to isolated fever or hypothermia. (See 'Clinical features' above.)
Isolation of a bacterial pathogen from the cerebrospinal fluid (CSF) in culture or with molecular methods confirms the diagnosis of bacterial meningitis. Concomitant blood cultures often are positive for the same organism as the CSF culture but can be negative in up to one-third of cases [2,22,40,50].
Pending culture results, neonates who have undergone evaluation for sepsis and meningitis should be hospitalized and treated with antibiotics for presumed sepsis and meningitis. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)
The CSF culture may be negative in some neonates with bacterial meningitis whose lumbar puncture (LP) was delayed until after antibiotic administration (eg, unstable, critically ill neonates). In such neonates, a diagnosis of bacterial meningitis may be made if the initial blood culture grows a pathogen and the CSF obtained 24 to 36 hours after initiation of antibiotic therapy is abnormal (eg, neutrophilic pleocytosis, low glucose, and/or elevated protein).
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of neonatal sepsis and meningitis includes systemic viral, fungal, and parasitic infections and noninfectious causes of abnormal neurologic signs, temperature instability, and/or cardiorespiratory instability (table 2). The clinical history, disease course, and laboratory findings may help to distinguish neonatal meningitis from other infectious and noninfectious disorders. Ultimately, appropriate microbiologic testing is required to confirm the diagnosis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Differential diagnosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bacterial meningitis in infants and children" and "Society guideline links: Sepsis in neonates".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Bacterial meningitis is more common in the first month than at any other time of life. Risk factors for neonatal meningitis are largely the same as for neonatal sepsis more broadly (eg, low birth weight, preterm birth, premature and/or prolonged rupture of membranes, maternal intra-amniotic infection). (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors' and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Risk factors'.)
●Microbiology – Group B Streptococcus (GBS) and Escherichia coli are the most common causes of bacterial meningitis in neonates. (See 'Microbiology' above.)
●Clinical features – Signs of neonatal meningitis include (see 'Clinical features' above):
•Fever (rectal temperature >38°C) or hypothermia (rectal temperature <36°C)
•Irritability
•Lethargy
•Poor feeding or feeding intolerance
•Bulging fontanelle
•Nuchal rigidity is observed in a minority of affected infants
Neonatal meningitis should be suspected in any infant <1 month of age who presents with signs of sepsis since the early clinical features are indistinguishable.
●Evaluation – Evaluation of neonates with suspected sepsis or meningitis should include (see 'Evaluation' above):
•Review of the prenatal and birth history
•Complete physical examination
•Full laboratory evaluation for sepsis including:
-Complete blood count with differential (optional)
-Blood culture
-Urine culture (if ≥72 hours old)
-Lumbar puncture (LP) for cerebrospinal fluid (CSF) cell count, protein, glucose, Gram stain, culture, and molecular testing
●Interpretation of CSF parameters – Neonatal bacterial meningitis is characterized by the following CSF findings (see 'Interpretation of CSF parameters' above):
•CSF white blood cell (WBC) count >15 cells/microL with a neutrophilic predominance
•Elevated CSF protein
•Decreased CSF glucose
●Empiric therapy – Pending culture results, neonates who have undergone evaluation for sepsis and meningitis should be hospitalized and treated with parenteral antibiotics, as discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)
●Diagnosis – The diagnosis of neonatal bacterial meningitis is confirmed by isolation of a bacterial pathogen from the CSF by culture or molecular methods. If the LP is delayed until 24 to 36 hours after initiation of antibiotics, the diagnosis can be made on the basis of abnormal CSF parameters (eg, neutrophilic pleocytosis, low glucose, elevated protein) and isolation of a pathogen from the blood. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis of bacterial meningitis in the neonate includes infectious and noninfectious causes of abnormal neurologic findings, temperature instability, and/or cardiorespiratory instability (table 2). (See 'Differential diagnosis' above.)
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